Diabetes Mellitus in Ataxia-Telangiectasia, Fanconi Anemia, Xeroderma Pigmentosum, Common Variable Immune Deficiency, and Severe Combined Immune Deficiency Families

Abstract

The hypothesis that heterozygous carriers of genes for certain autosomal recessive syndromes may be predisposed to diabetes was tested by comparing diabetes incidence from age 20 to 69 yr in blood relatives to that in spouse controls among 7999 adult family members of patients with one of five autosomal recessive syndromes: ataxia-telangiectasia (A-T), Fanconi anemia (FA), xeroderma pigmentosum (XP), common variable immune deficiency (CVID), and severe combined immune deficiency (SCID). FA and A-T families were studied because earlier findings in family members and the frequency of diabetes in homozygotes suggested that heterozygotes might also be predisposed to diabetes. The XP, CVID, and SCID families were included to see what analysis of family data would reveal when there was no prior evidence for a gene-diabetes association. The diabetes rate ratios of 2.6 and 4.2 among FA and SCID females, respectively, were significantly elevated. For female FA heterozygotes specifically, the estimated relative risk of 5.1 for developing diabetes was also significantly elevated. Among males, the most pronounced, although not statistically significant, findings were an elevated rate ratio of 2.2 for A-T males and a low-rate ratio of 0.5 for CVID males. The results suggest that heterozygotes for some of the diabetes-associated autosomal recessive syndromes may themselves be predisposed to diabetes.

Fanconi Anemia Links Reactive Oxygen Species to Insulin Resistance and Obesity

“…Notably, the FA female heterozygote is about six times more likely to develop diabetes than the general population (28,41).…”

ATM Regulates Adipocyte Differentiation and Contributes to Glucose Homeostasis

“…A-T patients also exhibit poor weight gain, a progressive decrease in their BMI, and progressive dystrophy (Schubert et al, 2005). In addition to A-T patients, A-T carriers, who comprise an estimated 0.05%-0.1% of the normal population, suffer an increased risk of ischemic heart disease (Su and Swift, 2000) and diabetes (Morrell et al, 1986). As in A-T patients, glucose intolerance has been reported in Atm À/À , Atm +/À ApoE À/À , and Atm À/À ApoE À/À mice (Miles et al, 2007;Schneider et al, 2006); the Atm +/À ApoE À/À mouse model generates a state of insulin resistance similar to that observed in type 2 diabetes.…”

ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia

“…In cystic fibrosis, lung inflammation appears to be related to increases in resting metabolic rate. Acute exacerbations of the chronic lung disease increases resting metabolic rate, which returns to a basal level some weeks after the inflammation is treated [61]; similar factors are likely (but not proven) to be contributory in A-T. A-T causes extreme insulin resistance [62], but clinical diabetes seems to be diagnosed infrequently [63][64][65][66]; in a Turkish series of 160 patients somatic growth retardation was reported to be common, but only two patients had frank diabetes mellitus [67]. It is unclear whether the presence of diabetes also affects lung disease in any way, but diabetes should be borne in mind during peri-operative management (see later).…”